Abstract

Diabetes mellitus affects the pharmacokinetics of cytochrome P450 3A4/5 (CYP3A4/5) substrates. We evaluated the relationship between haemoglobin A1c (HbA1c) levels and the pharmacokinetics of controlled-release tacrolimus. This retrospective observational cohort study included kidney transplant recipients (>18 years) receiving controlled-release tacrolimus orally. CYP3A5 genotypes were categorized as expressers (*1/*1 or *1/*3) and non-expressers (*3/*3). Multiple linear regression analysis determined the predictors for trough concentration/dose-normalized by body weight (C/D) ratio of tacrolimus at 7 days, 6 months and 12 months after administration. Correlations between the C/D ratio and HbA1c levels at baseline, 6 and 12 months after tacrolimus initiation were evaluated with Bonferroni correction. Out of 42 patients (CYP3A5 expressers, n= 17, and non-expressers, n= 25), the multiple linear regression analysis showed that the C/D ratio on Day 7 was marginally higher in CYP3A5 non-expressers than in CYP3A5 expressers (r= .43, P= .028). Factors affecting the elevation of tacrolimus C/D ratio after 6 and 12 months of treatment were male sex and CYP3A5 non-expressers (r= .59, P< .001) and increased HbA1c levels and CYP3A5 non-expressers (r= .62, P< .001), respectively. The C/D ratio and HbA1c levels after 12 months was positively correlated in CYP3A5 non-expressers (y= 54.6x- 194.6, r= .63, P= .004, Bonferroni correction). Furthermore, intra-individual changes in the C/D ratio and HbA1c levels from 6 to 12 months were nearly correlated (y= 54.5x+ 20.2, r= .41, P= .036, Bonferroni correction). HbA1c and CYP3A5 genotypes might be considered to understand the inter- and intra-individual variability in blood tacrolimus concentrations after 6 months post-kidney transplantation.

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